A path towards better cancer drugs: Modeling interactions between antimitotic agents and tubulin

• Author / Creator

  Churchill, Cassandra D.M.

• Antimitotic agents, a class of cancer chemotherapies, target the tubulin protein in microtubules to suppress microtubule dynamics and affect the segregation of chromosomes during cell division. A variety of antimitotic agents are known, which range in status from clinically-approved agents to those in preclinical studies. For example, three clinically-approved taxanes are in use, while laulimalide has experienced many issues in preclinical studies. Regardless of the status of a compound, in many instances there is limited information regarding the ligand-tubulin interactions in the binding site, as well as the global effects on tubulin that result from the binding of the compound. Atomic-resolution models of ligand-tubulin interactions are necessary to develop an enhanced understanding of how these agents work. Using molecular modeling, methods derived from classical mechanics and quantum mechanics are used to investigate ligand-tubulin interactions on a local and global scale. The binding of laulimalide and laulimalide analogues to tubulin is examined using an expanded computational model and molecular mechanics, which provided the first atomistic model of laulimalide in a microtubule-like environment. Specific laulimalide-residue interactions were identified, indicating the importance of an intramolecular hydrogen bond, direct and water-mediated ligand-tubulin hydrogen bonds, and ligand-tubulin pi-pi interactions. A correlation was noted between cytotoxicity and select ligand-protein interactions, establishing a laulimalide pharmacophore that may be used in the design of novel laulimalide compounds. The importance of a specific macrocycle conformation was also established. Using the information gained from this computational model of the laulimalides, novel laulimalide-like compounds were also considered and their efficacy predicted, illustrating the utility of such a computational model. Despite the clinical success of the taxanes, the mechanism of action of this class of drugs remains elusive, making rational design of related compounds difficult. A classical model revealed that the taxanes adopt different conformations in the binding site, but bring about a similar allosteric effect on tubulin. For the first time, this allosteric effect was traced from the drug binding site, across the tubulin protein. This establishes a metric by which the efficacy of other taxane-domain binders may be ranked in future rational drug design studies using computational models. Quantum-mechanical descriptions of ligand-protein complexes are also obtained in this Thesis. The effects of electron correlation and implicit solvent are examined, and it is found that electron correlation plays a larger role in ranking taxane binding than the implicit solvent. The quantum-mechanical treatment also reveals that some ligand-residue interactions are destabilizing, a result that cannot be obtained through classical descriptions. The work in this Thesis provides significant insights into the binding of different microtubule-targeting agents to tubulin. Atomic-resolution models allow for enhanced examination of ligand-tubulin complexes. The results obtained in this Thesis will be useful in guiding future drug design strategies for novel compounds with enhanced activity.

• Subjects / Keywords

  • Computational chemistry
  • Taxanes
  • Microtubules
  • Laulimalide
  • Paclitaxel

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R35H7C78S

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.